Molecular mechanisms
As in muscle, vitamin D acts according to genomic and nongenomic pathways [
39‐
42]. VDR have been demonstrated in some parts of the brain, especially in the hippocampus, hypothalamus, and limbic system but also in cortical, subcortical and spinal motor zones [
70‐
78]. At the cellular level, these receptors are present on neurons and glial cells [
40‐
74].
Experimentally, in animals, vitamin D is involved in neurophysiology and regulates the metabolism of neurotransmitters including dopamine, acetylcholine, serotonin and gamma aminobutyric acid [
70,
78], and the synthesis of certain growth factors such as Nerve Growth Factor (NGF) or Glial cell line-derived neurotrophic factor (GDNF) [
70‐
77]. Vitamin D is also involved in the development and maturation of rodents brain [
70,
71,
75]. In addition to this central action, vitamin D also acts on the peripheral nervous system, as a reduction of nerve conduction velocity has been reported in the case of severe vitamin D insufficiency [
47].
Vitamin D is also involved in neuroprotection through immunomodulating, anti-ischemic and anti-oxidative properties. Indeed, trophic induction plays a neuroprotective role in cerebral ischemia [
79], as well as an anti-neurodegenerative role for dopaminergic cells in models of Parkinson's disease [
80]. Moreover, it seems that vitamin D plays a part in the cerebral processes of detoxification by interacting with reactive oxygen and nitrogen species in rat brain and by regulating the activity of γ-glutamyl transpeptidase [
81], a key enzyme in the antioxydative metabolism of glutathione. Concentrations around 0.1 to 100 nanomoles of 1,25(OH)D thus ensure an efficient protection of neurons against the direct effects of superoxyde ions and hydrogene peroxyde [
80]. Finally, VDR-dependent immunosuppressive effects, including increased concentrations of inflammatory cytokines, macrophages, polynuclears, as well as their sensitization to apoptotic signals, were described in the CNS [
70]. For illustration, in a model of mice with experimental allergic encephalitis, 1,25(OH)D inhibited autoimmune neurological processes [
82,
83].
Vitamin D could also be vasculoprotective since vitamin D insufficiency has been associated with incident cerebrovascular disease [
84]. For instance, atherosclerosis is a systemic inflammatory disease related to vitamin D insufficiency [
85]. C-Reactive Protein is a marker of inflammation and atherosclerosis regulated by Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) [
86], which secretions dose-dependently decreased in presence of vitamin D [
87]. Furthermore, vitamin D insufficiency could be a contributing factor to hypertension - a major determinant of the development of cerebrovascular diseases - by the suppression of the renin-angiotensin system expression in the juxtaglomerular apparatus [
88] and by an action on the arterial wall compliance [
88,
89].
All together, these properties could stabilize the neurophysiologic function and explain why the lack of functional VDR in the brain of VDR-knockout transgenic mice models was responsible for behavioral disorders due not only to an increased level of stress but also to severe motor disorders [
73,
78,
90‐
92]. For instance, the suppression of functional cerebral VDR in transgenic mice induced a decreased swimming capacity with fewer swimming movements, suggesting the essential role of vitamin D in motor control [
90].
Observation
Some clinical data in humans appear to support the hypothesis of a favorable action of vitamin D on cognitive function, especially attention, as Yaffe et al. [
93] observed, in a population of 8,333 women over the age of 65, that cognitive performance on frontal and attentional tests were lower in women with a low BMD or vertebral fractures, establishing a link between post-menopausal osteoporosis - related to vitamin D insufficiency - and cognitive decline. Although the hypothesis of a simple temporal relationship is possible in this study, the hypothesis of an action of vitamin D on cognitive function is highly likely [
94]. In particular, epidemiological studies revealed lower serum 25(OH)D concentrations in subjects with Alzheimer disease than in healthy subjects [
95,
96]. In addition, emerging analytical studies have brought new evidence [
94]. For instance, Wilkins et al. [
97] found a significant positive association between the serum 25(OH)D levels and the scores at the Clinical Dementia Rating and at the Short Blessed Test in 80 older subjects aged 65 and over, living at home (40 subjects with AD and 40 non-demented subjects). Additionally, Przybelski et al. [
98] and Oudshorn et al. [
99] highlighted an association with the Mini Mental Status Examination (MMSE) score. Similarly, Llewellyn et al. demonstrated among 1,766 non-demented subjects or with Mild Cognitive Impairment aged 78 years on average that the lowest 25(OH)D concentrations, the highest risk of pathological Abbreviated Mental Test score [
100]. In line with this, Annweiler et al. showed a 2-fold risk of global cognitive impairment (Pfeiffer's Short Portable Mental State Questionnaire) among 752 older women (mean age 82 years) [
101]. Finally, Buell et al. [
102] showed among 318 participants (mean age 73.5 years, 72.6% women) that 25(OH)D insufficiency was associated with more than twice the odds of all-cause dementia and of Alzheimer disease. In contrast, two studies found no significant association [
103,
104]. First, Jorde et al. have unsuccessfully explored the linear association of 25(OH)D with 6 specific cognitive functions (working memory, episodic memory, speed of information processing, language, executive functions and intelligence) in 148 older subjects with hyperparathyroidism (mean age 62 years, 46% women) [
103]. Second, McGrath et al. found no significant positive logistic association between the quintiles of serum 25(OH)D concentrations and several specific cognitive tasks among 4,747 adults between 20 and 59 years (Symbol-digit Substitution Coding Speed: attention and episodic memory; Serial Digit Learning Trials To Criterion: working memory) [
104].
From a prospective perspective, Slinin et al. [
105] highlighted a trend for an independent association between lower 25(OH)D levels and odds of cognitive decline by Modified Mini Mental State score among 1,604 men enrolled in the Osteoporotic Fractures in Men Study and followed for an average of 4.6 years. Additionally, Llewellyn et al. [
106] showed that low 25(OH)D levels were associated with substantial decline in MMSE score among 858 adults aged ≥65 years studied over a 6-year period.
Literature review shows that the choice of confounders is essential and could explain the divergences in results. Analyses should thus take into account a list of covariates such as depression or serum parathormone concentrations.
First, depressive mood is associated with both cognition and vitamin D. Indeed, depression by itself can mimic dementia - when people are depressed, they can have difficulty concentrating, which leads to forgetfulness - or is often part of dementia, or may cause by itself executive dysfunction [
107]. Additionally, a relationship between vitamin D deficiency and anxio-depressive disorders is likely since low serum 25(OH)D concentrations are closely associated with active mood disorders [
70] and have been proposed as the missing link between seasonal changes in photoperiod and seasonal mood swings [
70]. In line with this, one clinical trial supported the efficacy of vitamin D supplementation on mood disorders [
108]. Finally, accounting for depression is of primary importance while exploring the involvement of vitamin D-related cognitive functioning in locomotor function as depressed people are usually less active and loose muscle mass as well as sensorimotor performance [
70].
Second, vitamin D belongs a complex biological system, and its insufficiency causes an elevation of serum parathormone [
109]. Patients with primary hyperparathyroidism usually exhibit cognitive disorders [
109,
110], that could be reversed after parathyroidectomy [
110]. Moreover, in the Helsinki Ageing Study, high parathormone concentrations indicated an independent 2-fold risk for a five-year cognitive decline [
111]. The systemic microvascular disease involving cerebral vasculature together with hypercalcemia have been proposed to result in disruption of the blood brain barrier and accumulation of calcium deposits in brain tissue, leading to cognitive impairment [
111]. In vitro studies have also shown that parathormone increases intracellular calcium concentration and causes cell deterioration in the rodent hippocampal neurons [
112]. Furthermore, individual differences in the cell membrane ability to resist calcium influx have been hypothesized to cause the well-known but poorly understood variability of clinical symptoms in patients with hyperparathyroidism [
111].
Anyway and to the best of our knowledge, the association of hypovitaminosis D with global cognitive impairment persist after adjustment for these both covariables.
This association of vitamin D with global composite cognitive scores has been recently explained by executive function and processing speed impairments [
106,
113]. Amongst 1,080 subjects (mean age 75 years, 76% women) free of neuropsychiatric disorders (epilepsy, schizophrenia, bipolar disorder, mental retardation, brain tumors, Human Immunodeficiency Virus), Buell et al. found a significant positive linear association between serum 25(OH)D concentrations and scores in tests exploring executive functions (Trail Making Test: flexibility) and speed of information processing (Digit Symbol Coding) [
113]. In addition, Llewellyn et al. [
106] found a substantial decline on Trail-Making Test B among 858 adults 65 years or older enrolled in the InCHIANTI study and followed for an average of 5.2 years. Executive functions include all heterogeneous cognitive processes required in the regulation of cognitive activity during the treatment of complex and/or new and/or conflictual tasks [
114]. These frontal and attention functions are precisely those which enable us to adapt our behaviors - such as walking - to expected or unforeseen situations of daily living. They are therefore of prime importance for determining posture, navigation abilities and locomotor performance. For instance, they have direct impact on selection of postural control strategies when older adults encounter specific temporal and environmental constraints which could place them at risk for falls [
114‐
116].